scholarly journals Chamber-enriched gene expression profiles in failing human hearts with reduced ejection fraction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xin Luo ◽  
Jun Yin ◽  
Denise Dwyer ◽  
Tracy Yamawaki ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Human Genetics ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Left Heart ◽  
Reduced Ejection Fraction ◽  
Cell Type Composition ◽  
Type Composition ◽  
Underlying Mechanisms

AbstractHeart failure with reduced ejection fraction (HFrEF) constitutes 50% of HF hospitalizations and is characterized by high rates of mortality. To explore the underlying mechanisms of HFrEF etiology and progression, we studied the molecular and cellular differences in four chambers of non-failing (NF, n = 10) and HFrEF (n = 12) human hearts. We identified 333 genes enriched within NF heart subregions and often associated with cardiovascular disease GWAS variants. Expression analysis of HFrEF tissues revealed extensive disease-associated transcriptional and signaling alterations in left atrium (LA) and left ventricle (LV). Common left heart HFrEF pathologies included mitochondrial dysfunction, cardiac hypertrophy and fibrosis. Oxidative stress and cardiac necrosis pathways were prominent within LV, whereas TGF-beta signaling was evident within LA. Cell type composition was estimated by deconvolution and revealed that HFrEF samples had smaller percentage of cardiomyocytes within the left heart, higher representation of fibroblasts within LA and perivascular cells within the left heart relative to NF samples. We identified essential modules associated with HFrEF pathology and linked transcriptome discoveries with human genetics findings. This study contributes to a growing body of knowledge describing chamber-specific transcriptomics and revealed genes and pathways that are associated with heart failure pathophysiology, which may aid in therapeutic target discovery.

scholarly journals Suppression of Tumourigenicity 2 in Heart Failure With Preserved Ejection Fraction

2020 ◽  
Vol 6 ◽  
Author(s):  
Veronika Zach ◽  
Felix Lucas Bähr ◽  
Frank Edelmann
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Incidence Rates ◽  
Current Evidence ◽  
Ageing Population ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Novel Biomarkers ◽  
Underlying Mechanisms ◽  
Receptor Family

Heart failure (HF), with steadily increasing incidence rates and mortality in an ageing population, represents a major challenge. Evidence suggests that more than half of all patients with a diagnosis of HF suffer from HF with preserved ejection fraction (HFpEF). Emerging novel biomarkers to improve and potentially guide the treatment of HFpEF are the subject of discussion. One of these biomarkers is suppression of tumourigenicity 2 (ST2), a member of the interleukin (IL)-1 receptor family, binding to IL-33. Its two main isoforms – soluble ST2 (sST2) and transmembrane ST2 (ST2L) – show opposite effects in cardiovascular diseases. While the ST2L/IL-33 interaction is considered as being cardioprotective, sST2 antagonises this beneficial effect by competing for binding to IL-33. Recent studies show that elevated levels of sST2 are associated with increased mortality in HF with reduced ejection fraction. Nevertheless, the significance of sST2 in HFpEF remains uncertain. This article aims to give an overview of the current evidence on sST2 in HFpEF with an emphasis on prognostic value, clinical association and interaction with HF treatment. The authors conclude that sST2 is a promising biomarker in HFpEF. However, further research is needed to fully understand underlying mechanisms and ultimately assess its full value.

scholarly journals Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function

2019 ◽  
Vol 316 (5) ◽  
pp. H1167-H1177 ◽  
Author(s):  
Jennifer L. Philip ◽  
Thomas M. Murphy ◽  
David A. Schreier ◽  
Sydney Stevens ◽  
Diana M. Tabima ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Pulmonary Fibrosis ◽  
Ejection Fraction ◽  
Right Ventricle ◽  
Pulmonary Vasculature ◽  
Left Heart ◽  
Left Heart Failure ◽  
Reduced Ejection Fraction ◽  
Pathologic Features

Left heart failure (LHF) is the most common cause of pulmonary hypertension, which confers an increase in morbidity and mortality in this context. Pulmonary vascular resistance has prognostic value in LHF, but otherwise the mechanical consequences of LHF for the pulmonary vasculature and right ventricle (RV) remain unknown. We sought to investigate mechanical mechanisms of pulmonary vascular and RV dysfunction in a rodent model of LHF to address the knowledge gaps in understanding disease pathophysiology. LHF was created using a left anterior descending artery ligation to cause myocardial infarction (MI) in mice. Sham animals underwent thoracotomy alone. Echocardiography demonstrated increased left ventricle (LV) volumes and decreased ejection fraction at 4 wk post-MI that did not normalize by 12 wk post-MI. Elevation of LV diastolic pressure and RV systolic pressure at 12 wk post-MI demonstrated pulmonary hypertension (PH) due to LHF. There was increased pulmonary arterial elastance and pulmonary vascular resistance associated with perivascular fibrosis without other remodeling. There was also RV contractile dysfunction with a 35% decrease in RV end-systolic elastance and 66% decrease in ventricular-vascular coupling. In this model of PH due to LHF with reduced ejection fraction, pulmonary fibrosis contributes to increased RV afterload, and loss of RV contractility contributes to RV dysfunction. These are key pathologic features of human PH secondary to LHF. In the future, novel therapeutic strategies aimed at preventing pulmonary vascular mechanical changes and RV dysfunction in the context of LHF can be tested using this model. NEW & NOTEWORTHY In this study, we investigate the mechanical consequences of left heart failure with reduced ejection fraction for the pulmonary vasculature and right ventricle. Using comprehensive functional analyses of the cardiopulmonary system in vivo and ex vivo, we demonstrate that pulmonary fibrosis contributes to increased RV afterload and loss of RV contractility contributes to RV dysfunction. Thus this model recapitulates key pathologic features of human pulmonary hypertension-left heart failure and offers a robust platform for future investigations.

scholarly journals Reverse remodelling of the heart after atrial fibrillation ablation in patients with heart failure with reduced ejection fraction

Kardiologiia ◽  
2019 ◽  
Vol 59 (8S) ◽  
pp. 37-43
Author(s):  
N. Z. Gasimova ◽  
E. N. Mikhaylov ◽  
V. S. Orshanskaya ◽  
A. V. Kamenev ◽  
R. B. Tatarsky ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Left Ventricle ◽  
Ejection Fraction ◽  
Reverse Remodeling ◽  
Left Heart ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure

Aim. To evaluate the effect of atrial fibrillation (AF) catheter ablation (CA) on long-term freedom from AF and left heart reverse remodeling in patients with heart failure with reduced ejection fraction (HFrEF).Methods. There were 47 patients (mean age 53.3 ± 10 years, 39 males) enrolled into single-center observational study, with left ventricular ejection fraction (LVEF) <40 %. Patients underwent CA for AF refractory to antiarrhythmic drugs. Baseline clinical data and diagnostic tests results were obtained during personal visits and / or via secure telemedical services. Personal contact with evaluation of recurrence of AF and echocardiographic values was performed with 30 (64 %) patients.Results. Paroxysmal AF was present in 12 (40 %) patients, persistent – in 18 (60 %). During mean follow-up of 3 years (0.5–6 years) redo ablation was performed in 9 patients (30 %) with average number of 1.3 procedures per patient. At 6 months 24 (80 %) patients were free from AF, at last follow-up – 16 (53 %). The mean time to first recurrence following CA was 15.6±13.3 months. Follow-up echocardiography revealed significant LVEF improvement (р<0,0001), reduction of left atrium size (р<0,0001), left ventricle end-diastolic volume (р<0,002) and left ventricle endsystolic volume (p<0,0001) and mitral regurgitation (р=0,001).Conclusion. AF CA in patients with HFrEF is associated with improvement in systolic function and left heart reverse remodeling. Durable long-term antiarrhythmic effect often requires repeated procedures.

scholarly journals Large Animal Models of Heart Failure: Reduced vs. Preserved Ejection Fraction

Animals ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1906 ◽  
Author(s):  
Christopher J. Charles ◽  
Miriam T. Rademaker ◽  
Nicola J. A. Scott ◽  
A. Mark Richards
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Animal Models ◽  
Ejection Fraction ◽  
Treatment Options ◽  
Large Animal ◽  
Reduced Ejection Fraction ◽  
Large Animal Models ◽  
Sampling Protocols ◽  
Underlying Mechanisms

Heart failure (HF) is the final common end point of multiple metabolic and cardiovascular diseases and imposes a significant health care burden worldwide. Despite significant improvements in clinical management and outcomes, morbidity and mortality remain high and there remains an indisputable need for improved treatment options. The pathophysiology of HF is complex and covers a spectrum of clinical presentations from HF with reduced ejection fraction (HFrEF) (≤40% EF) through to HF with preserved EF (HFpEF), with HFpEF patients demonstrating a reduced ability of the heart to relax despite an EF maintained above 50%. Prior to the last decade, the majority of clinical trials and animal models addressed HFrEF. Despite growing efforts recently to understand underlying mechanisms of HFpEF and find effective therapies for its treatment, clinical trials in patients with HFpEF have failed to demonstrate improvements in mortality. A significant obstacle to therapeutic innovation in HFpEF is the absence of preclinical models including large animal models which, unlike rodents, permit detailed instrumentation and extensive imaging and sampling protocols. Although several large animal models of HFpEF have been reported, none fulfil all the features present in human disease and few demonstrate progression to frank decompensated HF. This review summarizes well-established models of HFrEF in pigs, dogs and sheep and discusses attempts to date to model HFpEF in these species.

scholarly journals Massive single-cell RNA-seq analysis and imputation via deep learning

2018 ◽  
Author(s):  
Yue Deng ◽  
Feng Bao ◽  
Qionghai Dai ◽  
Lani F. Wu ◽  
Steven J. Altschuler
Keyword(s):  
Deep Learning ◽  
Single Cell ◽  
Large Scale ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Rna Seq ◽  
Fine Grained ◽  
Cell Type Composition ◽  
Type Composition ◽  
Cell Gene Expression

Recent advances in large-scale single cell RNA-seq enable fine-grained characterization of phenotypically distinct cellular states within heterogeneous tissues. We present scScope, a scalable deep-learning based approach that can accurately and rapidly identify cell-type composition from millions of noisy single-cell gene-expression profiles.

scholarly journals Exercise limitations in heart failure with reduced and preserved ejection fraction

2018 ◽  
Vol 124 (1) ◽  
pp. 208-224 ◽  
Author(s):  
David C. Poole ◽  
Russell S. Richardson ◽  
Mark J. Haykowsky ◽  
Daniel M. Hirai ◽  
Timothy I. Musch
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Ejection Fraction ◽  
Clinical Intervention ◽  
Exercise Intolerance ◽  
Transport Pathway ◽  
Phosphorescence Quenching ◽  
Reduced Ejection Fraction ◽  
Emerging Therapies ◽  
Underlying Mechanisms

The hallmark symptom of chronic heart failure (HF) is severe exercise intolerance. Impaired perfusive and diffusive O2 transport are two of the major determinants of reduced physical capacity and lowered maximal O2 uptake in patients with HF. It has now become evident that this syndrome manifests at least two different phenotypic variations: heart failure with preserved or reduced ejection fraction (HFpEF and HFrEF, respectively). Unlike HFrEF, however, there is currently limited understanding of HFpEF pathophysiology, leading to a lack of effective pharmacological treatments for this subpopulation. This brief review focuses on the disturbances within the O2 transport pathway resulting in limited exercise capacity in both HFpEF and HFrEF. Evidence from human and animal research reveals HF-induced impairments in both perfusive and diffusive O2 conductances identifying potential targets for clinical intervention. Specifically, utilization of different experimental approaches in humans (e.g., small vs. large muscle mass exercise) and animals (e.g., intravital microscopy and phosphorescence quenching) has provided important clues to elucidating these pathophysiological mechanisms. Adaptations within the skeletal muscle O2 delivery-utilization system following established and emerging therapies (e.g., exercise training and inorganic nitrate supplementation, respectively) are discussed. Resolution of the underlying mechanisms of skeletal muscle dysfunction and exercise intolerance is essential for the development and refinement of the most effective treatments for patients with HF.

scholarly journals A novel computational complete deconvolution method using RNA-seq data

2018 ◽  
Author(s):  
Kai Kang ◽  
Qian Meng ◽  
Igor Shats ◽  
David M. Umbach ◽  
Melissa Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Specific Gene ◽  
Rna Seq ◽  
Cell Type ◽  
Specific Gene Expression ◽  
Cell Type Composition ◽  
Type Composition ◽  
Cell Type Specific

AbstractThe cell type composition of many biological tissues varies widely across samples. Such sample heterogeneity hampers efforts to probe the role of each cell type in the tissue microenvironment. Current approaches that address this issue have drawbacks. Cell sorting or single-cell based experimental techniques disrupt in situ interactions and alter physiological status of cells in tissues. Computational methods are flexible and promising; but they often estimate either sample-specific proportions of each cell type or cell-type-specific gene expression profiles, not both, by requiring the other as input. We introduce a computational Complete Deconvolution method that can estimate both sample-specific proportions of each cell type and cell-type-specific gene expression profiles simultaneously using bulk RNA-Seq data only (CDSeq). We assessed our method’s performance using several synthetic and experimental mixtures of varied but known cell type composition and compared its performance to the performance of two state-of-the art deconvolution methods on the same mixtures. The results showed CDSeq can estimate both sample-specific proportions of each component cell type and cell-typespecificgene expression profiles with high accuracy. CDSeq holds promise for computationally deciphering complex mixtures of cell types, each with differing expression profiles, using RNA-seq data measured in bulk tissue (MATLAB code is available at https://github.com/kkang7/CDSeq_011).

Heart Failure with Preserved Ejection Fraction – A Review

2012 ◽  
Vol 9 (1) ◽  
pp. 90-95 ◽  
Author(s):  
Otto A Smiseth ◽  
Anders Opdahl ◽  
Espen Boe ◽  
Helge Skulstad
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Heart Failure ◽  
The Elderly ◽  
Left Ventricular ◽  
Filling Pressure ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Objective Evidence

Heart failure with preserved left ventricular ejection fraction (HF-PEF), sometimes named diastolic heart failure, is a common condition most frequently seen in the elderly and is associated with arterial hypertension and left ventricular (LV) hypertrophy. Symptoms are attributed to a stiff left ventricle with compensatory elevation of filling pressure and reduced ability to increase stroke volume by the Frank-Starling mechanism. LV interaction with stiff arteries aggravates these problems. Prognosis is almost as severe as for heart failure with reduced ejection fraction (HF-REF), in part reflecting co-morbidities. Before the diagnosis of HF-PEF is made, non-cardiac etiologies must be excluded. Due to the non-specific nature of heart failure symptoms, it is essential to search for objective evidence of diastolic dysfunction which, in the absence of invasive data, is done by echocardiography and demonstration of signs of elevated LV filling pressure, impaired LV relaxation, or increased LV diastolic stiffness. Antihypertensive treatment can effectively prevent HF-PEF. Treatment of HF-PEF is symptomatic, with similar drugs as in HF-REF.

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